Spinal fluid 5-methyltetrahydrofolate levels are normal in Rett syndrome.
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Adolescent↗
Biomedical subjects
P Humphreys
Publications and source records attributed to P Humphreys.
Cerebral sinovenous thrombosis in children.
BACKGROUND: Cerebral sinovenous thrombosis in children is a serious disorder, and information is needed about its prevention and treatment. METHODS: The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 at the 16 pediatric tertiary care centers in Canada. Children (newborn to 18 years of age) with symptoms and radiographic confirmation of sinovenous thrombosis were included. RESULTS: During the first six years of the registry, 160 consecutive children with sinovenous thrombosis were enrolled, and the incidence of the disorder was 0.67 cases per 100,000 children per year. Neonates were most commonly affected. Fifty-eight percent of the children had seizures, 76 percent had diffuse neurologic signs, and 42 percent had focal neurologic signs. Risk factors included head and neck disorders (in 29 percent), acute systemic illnesses (in 54 percent), chronic systemic diseases (in 36 percent), and prothrombotic states (in 41 percent). Venous infarcts occurred in 41 percent of the children. Fifty-three percent of the children received antithrombotic agents. Neurologic deficits were present in 38 percent of the children, and 8 percent died; half the deaths were due to sinovenous thrombosis. Predictors of adverse neurologic outcomes were seizures at presentation and venous infarcts. CONCLUSIONS: Sinovenous thrombosis in children affects primarily neonates and results in neurologic impairment or death in approximately half the cases. The occurrence of venous infarcts or seizures portends a poor outcome.
Adolescent↗
Cerebral vascular events associated with ulcerative colitis in children.
Although peripheral vascular thrombic events are recognized as a serious extra-intestinal complication of inflammatory bowel disease, the occurrence of cerebral vascular events in association with acute exacerbations of this group of diseases is rare. In this article, relevant literature is reviewed and three children, 5, 12, and 13 years of age, who presented with clinical and magnetic resonance imaging evidence of an acute cerebrovascular event in association with an acute exacerbation of their inflammatory bowel disease are described. Except for the presence of anemia, hematologic and coagulation studies were unremarkable, and a search for evidence of a systemic vasculitis proved negative.
Adolescent↗
Ultrastructural analysis of spinal motoneurones from mice treated with IgG from ALS patients, healthy individuals, or disease controls.
Reports that ALS-IgG injected into mice results in ultrastructural abnormalities and enhanced deposition of Ca(2+) in their spinal motoneurones are unverified. To obtain verification, affinity purified IgG's from ten healthy subjects, seventeen ALS patients and eight disease controls (e.g. cases of LEMS, MS,) were injected into groups of mice in 4 daily doses by either i/m injection, or i/p (Total doses, 2-4 mg i/p, 1 mg i/m). Immunocytochemistry identified human IgG in lumbar motoneurones 48 h after the final dose. Their morphology was examined by EM and intraneuronal Ca2+ was revealed by oxylate-pyroantimonate histochemistry and its identity verified by 2 degrees emission spectroscopy. In the EM, motoneurones of non-injected mice, and mice receiving healthy IgGs had a lucent cytoplasm, intact mitochondria, and Golgi complexes comprising stacks of narrow ER. About 40% of Nissl bodies comprised alternate rER lamellae and polyribosome arrays (Type 1 structure): 10% formed polyribosome clusters (Type 3). Mitochondria, Golgi ER and presynaptic terminals contained Ca(2+) associated pyroantimonate. I/m and i/p ALS-IgG produced similar results. Some ALS IgGs (i.e. patients) produced electron dense degenerative cytology: all promoted fragmented and distended Golgi ER, polyribosmal hyperplasia, reduced numbers of Type I but raised numbers of Types 2 and 3 Nissl bodies, and a greater proportion of Golgi ER and presynaptic terminals containing Ca(2+)-antimonate. With 4/8 disease control IgGs motoneurones had normal Golgi and Nissl body organisation but dilated rER. Ca2+ content was normal. Remaining IgGs produced normal ultrastructure. Results support claims that ALS-IgG may be cytotoxic, and that it enhances the Ca(2+) content of motoneurones and synaptic terminals.
Adult↗
Analysis of cerebrocortical neuronal migration in three-dimensional fetal mouse cerebral explants: comparison with in vivo.
Organotypic cultures of cerebral mantle offer a useful method for in vitro investigation of mechanisms involved in the migration of neuronal precursors to the neocortex. Studies reported to-date have indicated that, while neurons continue to migrate in cerebral explant cultures for a few days, they eventually stop migrating and fail to reach their pre-programmed destinations and thus distinct layers fail to develop within the cortical plate. Hypothesizing that this migrational arrest stemmed, in part, from severe distortion and flattening of explants in the roller-tube culture method used in previous studies by others, we studied neocortical neuronal migration using a recently developed three-dimensional explant culture system. Explants 300-350 microm thick were derived from E16 fetal mouse cerebrum 24 h following administration of 5-bromodeoxyuridine (BrdU), encased in collagen, placed on porous membranes, and alternately exposed to medium and air on a rocking platform. Cultures were maintained for 7, 11 and 14 days, then analyzed for the location of BrdU-labeled cells. Newborn mice labeled at E15 and analyzed at P1 and P9 served as controls. In the explants, labeled cells continued to migrate into the cortical plate until 11 days in culture, at which point the ventricular zone had disappeared and two distinct cortical cell layers sometimes developed. BrdU-labeled cells were present throughout the cortical plate, particularly the mid portion. In P9 controls, five distinct cortical layers were present with labeled cells mostly in the outer half (layers II, III). Thus, preservation of three-dimensional tissue integrity in culture was accompanied by a modest improvement in migration of neurons to the neocortex in comparison with previous reports. The fact that normal layer formation failed to develop in thick explants suggests that factors other than tissue distortion contribute to this outcome.
Aging↗
Hemiparetic cerebral palsy: clinical pattern and imaging in prediction of outcome.
BACKGROUND: Hemiparetic cerebral palsy (HCP) is described as having two main forms: arm-dominant, associated with large cortical/subcortical lesions; leg-dominant, associated with lesions of central white matter. Epilepsy and cognitive deficits are common in the former pattern and rare in the latter. Some authors have recommended routine imaging studies in children with HCP as an assessment of etiology and a predictor of outcome. The present study compares the relative values of clinical analysis and imaging in predicting epilepsy and cognitive disabilities. METHODS: Forty-one consecutive patients with HCP underwent careful clinical assessment and imaging studies (primarily computed tomography) and were followed prospectively for the development of recurrent afebrile seizures and academic difficulties. RESULTS: Twenty of the 41 patients (48.8%) were arm-dominant, 14/41 (34.1%) leg-dominant, and 7/41 (17.1%) proportional (arm = leg). The principal imaging findings were: arm-dominant patients - large arterial infarcts, porencephalic cysts, brain malformations; leg-dominant - periventricular leukomalacia; proportional - porencephaly. Arm-dominant hemiparesis and radiologic evidence of cortical pathology were both predictive of cognitive deficits (odds ratios 14.2 [95% CI 2.6, 75.8] and 5.7 [95% CI 1.4. 22.3] respectively). For the development of epilepsy, both evaluation techniques were again predictive, with imaging findings of cortical pathology being particularly powerful (clinical pattern OR 18.0 [95% CI 3.0, 107.7]; imaging OR 80.7 [95% CI 8.5, 767.3]). CONCLUSIONS: In this study, the clinical pattern of HCP and the radiological findings were both predictive of outcome, with absence of cortical pathology on imaging being particularly predictive for the absence of epilepsy. While the clinical pattern, in isolation, appears helpful in predicting outcome, our results suggest that both evaluation tools have important roles to play in the evaluation of HCP patients.
Adult↗
Time-dependent alterations in NOS1 immunoreactivity in feline pudendal motoneurons following retrograde axonal transport of diphtheria toxin.
Neuronal nitric oxide synthase immunoreactivity (NOS1-ir) in sacral somatic motor neurons of normal adult cats was compared with NOS1-ir in cats surviving 1 to 10 weeks after injection of the ADP-ribosylating protein diphtheria toxin (DTX) into one-half of the external anal sphincter. Levels of immunostaining were measured by microdensitometry. In non-operated cats, 60% of motor neurons in the ventrolateral (VL) and Onuf's nucleus (ON) showed high levels of NOS1-ir with lower NOS1-ir in 40%. Intramuscular injection of DTX caused cytopathology in motoneurons in ON, but not in VL with onset at 1 week, and regression by 10 weeks. Immunocytochemistry and microdensitometry disclosed an associated rise in levels of NOS1-ir in both the ipsilateral and contralateral ON at 1 week, which persisted up to 4 weeks, but reduced to normality by 10 weeks. Simultaneous neuronal swelling in ON precluded raised staining intensity being an artifact of neuronal atrophy. Despite restriction of cytopathology to ON, motoneurons in VL also exhibited acute elevation with subsequent normalisation of NOS1-ir over an identical time-course. Conclusions. Since DTX inhibits protein synthesis, (i) activation of NOS1 in acute toxicity probably reflects raised intracellular calcium due to loss of calcium homeostasis; (ii) the bilateral response in ON may indicate uptake of DTX by contralateral pudendal axons crossing the sphincter midline; and (iii) raised NOS1-ir in VL indicates a wider response in nuclei synaptically coupled to ON. Recovery of neuronal morphology and normalisation of NOS1-ir in sublethal toxicity contrast with the protracted elevation of NOS1-ir reported by others following axonal lesions associated with neuronal death and muscle target deprivation.
Animals↗
Ketogenic diet in the treatment of refractory epilepsy in childhood.
There has been renewed interest in the ketogenic diet in the treatment of medically refractory seizure disorders in childhood. This article reports the results of a retrospective chart review of 52 patients who were treated with the ketogenic diet. The vast majority (49 of 52) were treated with the classic 4:1 diet. Seizure control improved in 67.3% of patients with complete abolition of seizures in six. Adverse reactions were uncommon and included the development of renal stones, gall bladder stones, and hypoproteinemia in one patient each. Routine biochemical screening during the diet did not identify or prevent adverse events. The authors' experiences with the diet emphasize the need for close ongoing medical and dietary supervision.
Adolescent↗
Protracted elevation of neuronal nitric oxide synthase immunoreactivity in axotomised adult pudendal motor neurons.
Neuronal nitric oxide synthase immunoreactivity (NOS1-ir) in sacral motor neurons of normal adult cats was compared with that in cats surviving 1-10 wk after unilateral transection and ligation of the pudendal nerve. Levels of immunostaining were measured by microdensitometry. In nonoperated cats 60% of motor neurons in the ventrolateral nucleus (VL) and Onuf's nucleus (ON) showed high levels of NOS1-ir with lower NOS1-ir in 40%. Following axotomy, motor neurons in ON on both sides of the cord showed an acute rise in mean level of NOS1-ir at 1 wk, with a further increase at 2 wk. Mean levels of NOS1-ir in the ipsilateral and contralateral ON remained elevated at 10 wk after axotomy. Elevation of NOS1-ir occurred in the VL with a similar time-course to that in ON, implying a wider response in motor nuclei synaptically coupled to ON. Measurements of neuronal size in ON and VL revealed an increase in neuronal size in ON but not VL, indicating increased NOSI-ir in ON was not an artifact of neuronal atrophy. The proportion of motor neurons in ON and VL possessing higher levels of NOS1-ir increased from 60% in controls to 100% at 2-3 wk postaxotomy. The proportion slightly declined by 8 wk due to re-emergence of motor neurons exhibiting low NOS1-ir, but remained greater than normal at 10 wk in both nuclei. Based on evidence from related analyses of synaptology, we argue that acute axotomy induced alterations in presynaptic complement which increased overall Ca2+ influx and thereby stimulated NOS1-ir.
Anal Canal↗
Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif.
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Adolescent↗
Comparative analysis of nitric oxide synthase immunoreactivity in the sacral spinal cord of the cat, macaque and human.
Nitric oxide synthase immunoreactivity (bNOS-ir) was examined in the sacral spinal cord of the cat, macaque monkey and human using an antibody to the c-terminal region of neuronal NOS. In S2 of all 3 species NOS-ir was identified in both dorsal and ventral horns. In cat, monkey and human, bNOS-r occurred in sensory neurons of superficial laminae and the base of the dorsal horn, in autonomic neurons around the central canal and in the intermediolateral sacral spinal nucleus. In all 3 species, a large proportion of somatic motor nuclei in the ventromedial (VM), ventrolateral (VL) nuclei, and Onuf's nucleus (ON) showed high bNOS-ir, while others exhibited markedly lower immunoreactivity. Validatory experiments showed separate cellular localisation for bNOS, inducible NOS (iNOS), and endothelial NOS (eNOS) with only bNOS being localised to neuronal perikarya. Comparative morphometric analyses of the relative proportions and diameters of motor neurons in the VL, VM and ON exhibiting high and low levels of bNOS-ir revealed statistically significant differences in proportions in individual nuclei, and differences in size were generally not statistically significant. Finally, a comparison between cat sacral and thoracic spinal cord showed bNOS-ir in motor neurons of S2 was subject to less animal and rostrocaudal segment variation than in T10.
Anal Canal↗
DRINK: a biogeochemical source term model for low level radioactive waste disposal sites.
Interactions between element chemistry and the ambient geochemistry play a significant role in the control of radionuclide migration in the geosphere. These same interactions influence radionuclide release from near surface, low level radioactive waste, disposal sites once physical containment has degraded. In situations where LLW contains significant amounts of metal and organic materials such as cellulose, microbial degradation in conjunction with corrosion can significantly perturb the ambient geochemistry. These processes typically produce a transition from oxidising to reducing conditions and can influence radionuclide migration through changes in both the dominant radionuclide species and mineral phases. The DRINK (DRIgg Near field Kinetic) code is a biogeochemical transport code designed to simulate the long term evolution of the UK low level radioactive waste disposal site at Drigg. Drigg is the UK's principal solid low level radioactive waste disposal site and has been receiving waste since 1959. The interaction between microbial activity, the ambient geochemistry and radionuclide chemistry is central to the DRINK approach with the development of the ambient pH, redox potential and bulk geochemistry being directly influenced by microbial activity. This paper describes the microbial aspects of the code, site data underpinning the microbial model, the microbiology/chemistry interface and provides an example of the code in action.
Environmental Microbiology↗
Three-dimensional cultures of fetal mouse cerebral cortex in a collagen matrix.
A 3-dimensional tissue culture system for fetal mouse cerebral cortex was devised in order to study neuronal migration in vitro. The dorsolateral cerebral mantle of E16 mouse was dissected into slices of 250-350 microns. Explants were embedded in a matrix formed of thin layers of collagen gel above and below the tissue. The optimal conditions for maintaining explant survival within the matrix included (1) placing the explants on membrane inserts with large (70 microns) pores which permits access of nutrient to the cultures from below as well as from above, and (2) intermittent exposure of the explants to ambient oxygen (20% O2 with 5% CO2) by partially covering the upper surface with medium and placing the cultures on a rocking platform. Thickness measurements of serially sectioned intact cultures at 6 days in vitro ranged from 128 to 210 microns (average: 172 microns). In intact explants, maintained for up to 14 days in vitro, the preservation of neurones, neuronal subtypes and glia was confirmed with immunofluorescence staining for neurone-specific nucleoprotein (NeuN), microtubule-associated protein (MAP-2), a glutamate receptor subunit (GluR 1), GABA and glial fibrillary acidic protein (GFAP) respectively. Some cortical differentiation was obtained in vitro, at 6 days, with the development of upper and lower cortical layers, similar to that seen in an P1 animal.
Animals↗
Diversity in localisation of nitric oxide synthase antigen and NADPH-diaphorase histochemical staining in sacral somatic motor neurones of the cat.
Nitric oxide synthase (NOS) immunoreactivity occurred in about 60% of ventromedial, ventrolateral, and sphincteric motoneurones in cat sacral spinal cord. Proportions of sacral motoneurones histochemically stained for NADPH-diaphorase, were similar, and equivalent in size to those immunoreactive for NOS, suggesting co-localisation of diaphorase and NOS. Double staining techniques revealed that NOS co-localised with NADPH-diaphorase in approximately 60% of sacral motoneurones. Some remaining motoneurones exhibited neither NOS nor NADPH-diaphorase, while others exhibited only NOS or NADPH-diaphorase, indicating phenotypic differences among sacral motoneurones.
Animals↗
Incidence of Guillain-Barré syndrome in Ontario and Quebec, 1983-1989, using hospital service databases.
To determine the incidence of Guillain-Barré syndrome (GBS) in the Canadian provinces of Ontario and Quebec during 1983-1989 and to demonstrate the feasibility of measuring the incidence of GBS through internal record linkage of Canadian hospital service data, we conducted a record linkage study. This study used the databases of the Hospital Medical Records Institute and the Ministère de la santé et des services sociaux du Québec. We extracted records containing the International Classification of Diseases, 9th revision, code for GBS or a diagnosis likely to harbor misclassified GBS cases from each database and linked them internally using computerized algorithms. We identified a total of 1,302 and 1,031 incident cases of GBS admitted to Ontario and Quebec hospitals, respectively. The calculated mean annual GBS incidence rate in each province, after age and sex standardization to the 1986 Canadian census population, was 2.02 per 100,000 person-years in Ontario and 2.30 per 100,000 person-years in Quebec. Chart reviews revealed that the false-positive diagnosis rate might be as high as 0.26 per 100,000 person-years in Ontario and 0.21 per 100,000 person-years in Quebec. With adjustment for these false-positive rates, the incidence rate of GBS becomes 1.51 per 100,000 person-years and 1.78 per 100,000 person-years in Ontario and Quebec, respectively. In both provinces, the incidence rate was higher in older age strata (70-80 years) and in males. We saw no seasonal or geographic pattern.
Adolescent↗
Chromosome 4q locus associated with insulin resistance in Pima Indians. Studies in three European NIDDM populations.
Markers on chromosome 4q have recently been shown to be associated with insulin resistance in Pima Indians, a population in which insulin resistance precedes and predicts the development of non-insulin-dependent diabetes mellitus (NIDDM). To examine whether genes in this region could play a major role in susceptibility to NIDDM in other populations, we have examined the allele frequencies of a trinucleotide repeat near the fatty acid-binding protein 2 (FABP2) gene on 4q28-31 in three European populations: Finnish, U.K. Caucasian, and Welsh. The U.K. NIDDM population was selected for insulin resistance by studying patients whose obesity-corrected fasting plasma insulin before treatment was above the 98th percentile. Seven alleles were detected. On cross-tabulation analysis, there were no significant associations between allele frequencies and glucose intolerance in any of the populations. Log-linear analysis of the results from all three populations suggested a moderately significant interaction of glucose tolerance status (normal versus diabetic) and the FABP2 allele (partial chi 2 = 24, df 6, P = 0.027). The parameter describing the interaction of allele A3 and glucose tolerance status was the only such parameter differing significantly from zero (z-score +2.003, P = 0.046). In both the Finnish and U.K. population, the A3 allele was found approximately twice as frequently in NIDDM than in control subjects (Finnish control subjects, impaired glucose tolerance, and NIDDM: 12.2, 22.4, and 26.6%, respectively; U.K. control subjects and NIDDM: 7.8 and 14.6%, respectively). In the Finnish populations, no associations were found between FABP2 alleles and plasma insulin levels or with homeostatic model assessment (HOMA) estimates of beta-cell function and insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Freezing lesions of the developing rat brain: a model for cerebrocortical microgyria.
Cerebrocortical microgyri were induced by placing a freezing probe on the skull of P0 and P1 rat pups. Freezing lesions resulted in laminar necrosis of the infragranular layers and the subsequent migration of supragranular neurons through the region of damage. The result was most often a region of four-layered microgyric cortex consisting of a molecular layer, a thickened layer ii, a lamina dissecans (corresponding to the necrotized layers IV, V, and VIa), and a neuronal layer iv which corresponded to layer VIb of the intact cortex. Immunocytochemical investigation of the microgyric cortex with antibodies to neurofilament, glial fibrillary acidic protein and glutamate showed more widespread disruption of neocortical architecture than could be seen from Nissl preparations. In contrast, vasoactive intestinal peptide-containing neuronal bodies appeared to be distributed normally in the microgyric region although their processes were sometimes distorted. These results are considered in the light of previous research on induced microgyria, and possible implications for the behavioral consequences of focal, developmental neuropathologic lesions are discussed.
Animals↗
Developmental dyslexia in women: neuropathological findings in three patients.
Brains from male cases with dyslexia show symmetry of the planum temporale and predominantly left-sided cerebrocortical microdysgenesis. We now report on three women with dyslexia. In all brains, the planum temporale was again symmetrical. Also, in two of the brains, multiple foci of cerebrocortical glial scarring were present. In both women, many of the scars were myelinated, suggesting origination during late intrauterine or early postnatal life. In one, scars were mainly left perisylvian and involved portions of the vascular border zone of the temporal cortex. In the other, scars were more numerous and occurred in the border zone of the anterior, middle, and posterior cerebral arteries symmetrically. All three cases showed to a variable extent brain warts, molecular layer ectopias, and focal architectonic dysplasia identical to those seen in the male cases. Two women had primary brain neoplasms, an oligodendroglioma and a low-grade astrocytoma, respectively, and two women showed small angiomas. Reexamination of previously reported male cases disclosed one with myelinated glial scars. Two control brains with asymmetrical plana temporale showed myelinated glial scars as well. The significance of the anatomical findings is discussed, and possible etiological factors are considered with known effects of autoimmune diseases on the nervous system.
Adult↗